Contributing to Biochemistry and Optoelectronics: Pyrrolo[1′,2′:2,3]imidazo[1,5-a]indoles and Cyclohepta[4,5]pyrrolo[1,2-c]pyrrolo[1,2-a]imidazoles via [3+2] Annulation of Acylethynylcycloalka[b]pyrroles with Δ1-Pyrrolines

Available pyrrolylalkynones with tetrahydroindolyl, cycloalkanopyrrolyl, and dihydrobenzo[g]indolyl moieties, acylethynylcycloalka[b]pyrroles, are readily annulated with Δ1-pyrrolines (MeCN/THF, 70 °C, 8 h) to afford a series of novel pyrrolo[1′,2′:2,3]imidazo[1,5-a]indoles and cyclohepta[4,5]pyrrolo[1,2-c]pyrrolo[1,2-a]imidazoles functionalized with an acylethenyl group in up to an 81% yield. This original synthetic approach contributes to the arsenal of chemical methods promoting drug discovery. Photophysical studies show that some of the synthesized compounds, e.g., benzo[g]pyrroloimidazoindoles, are prospective candidates for TADF emitters of OLED.


Results and Discussion
As a model for primary optimization, the reaction of benzoylethynyltetrahydroindole 1a with pyrroline 4a, conveniently handled as its trimer, has been chosen ( Table 1).

Results and Discussion
As a model for primary optimization, the reaction of benzoylethynyltetrahydroindole 1a with pyrroline 4a, conveniently handled as its trimer, has been chosen (Table 1). Although the reaction in MeOH was completed within 24 h at room temperature (starting 1a was entirely consumed), the yield of product 5a did not exceed 11% (entry 1). In this case, the major products were acetyltetrahydroindole and methyl benzoate (60% and 72% yields). This result may be rationalized by a competitive nucleophilic addition of MeOH to 1a catalyzed by pyrroline 4a as a strong base. Nucleophilic addition of water to adduct A and the subsequent decomposition of the intermediate B gives diketone C, which adds a second molecule of MeOH and the intermediate D thus formed decomposes to acetyltetrahydroindole and methyl benzoate (Scheme 1).
a Reactions were carried out on 0.5 mmol scale, solvent 1 mL. b Determined by 1 H NMR with 2,3,5,6-tetramethylbenzene (durene) as the internal standard (isolated yield in parentheses). c Major products are acetyltetrahydroindole and methyl benzoate.
Although the reaction in MeOH was completed within 24 h at room temperature (starting 1a was entirely consumed), the yield of product 5a did not exceed 11% (entry 1). In this case, the major products were acetyltetrahydroindole and methyl benzoate (60% and 72% yields). This result may be rationalized by a competitive nucleophilic addition of MeOH to 1a catalyzed by pyrroline 4a as a strong base. Nucleophilic addition of water to adduct A and the subsequent decomposition of the intermediate B gives diketone C, which adds a second molecule of MeOH and the intermediate D thus formed decomposes to acetyltetrahydroindole and methyl benzoate (Scheme 1). Scheme 1. Proposed mechanism of Δ 1 -pyrroline-catalyzed reaction of acylethynyltetrahydroindole 1 with MeOH.
In MeCN (rt, 24 h), the reaction results in 12% yield of adduct 5a (entry 2) that can be attributed to the limited solubility of the starting materials in the reaction medium. Solvent screening revealed that a switch to MeCN/THF (1:1, v/v) gave better results (entries 2-4). Only a 1:1 ratio of MeCN/THF provided a homogenic reaction mixture. Therefore, other solvent ratios were not employed. After the short optimization of the reaction conditions, we found that, upon heating (70 °C), the comparable yields (80-81%, Table 1, entries 5, 6) were achieved in a shorter time than at room temperature (8 h vs. 72 h). The reaction conditions do not noticeably influence the ratio of E/Z isomers (~4:1). This prompted us to study the reaction of tetrahydroindole 1 with pyrrolines 4b-e under similar conditions (MeCN/THF, 70 °C, 8 h).
The experiments revealed that the reaction of tetrahydroindole 1a with pyrrolines 4b-d bearing the C2-alkyl group (Me, Et, Pr i ) under these conditions proceeded efficiently to afford pyrrolo[1′,2′:2,3]imidazo[1,5-a]indoles 5b-d in good to high yields (Scheme 2). There is a clear influence of the steric factors of the substituent at position 2 of pyrroline 4 on the yield of product 5: the more sterically compact methyl group compared to isopropyl group gives the product in a higher yield (79% vs. 60%). The presence of a tert-butyl group near the reaction center creates steric hindrance, preventing a more favorable orientation of the reagents during the reaction. In this case, Scheme 1. Proposed mechanism of ∆ 1 -pyrroline-catalyzed reaction of acylethynyltetrahydroindole 1 with MeOH.
In MeCN (rt, 24 h), the reaction results in 12% yield of adduct 5a (entry 2) that can be attributed to the limited solubility of the starting materials in the reaction medium. Solvent screening revealed that a switch to MeCN/THF (1:1, v/v) gave better results (entries 2-4). Only a 1:1 ratio of MeCN/THF provided a homogenic reaction mixture. Therefore, other solvent ratios were not employed. After the short optimization of the reaction conditions, we found that, upon heating (70 • C), the comparable yields (80-81%, Table 1, entries 5, 6) were achieved in a shorter time than at room temperature (8 h vs. 72 h). The reaction conditions do not noticeably influence the ratio of E/Z isomers (~4:1). This prompted us to study the reaction of tetrahydroindole 1 with pyrrolines 4b-e under similar conditions (MeCN/THF, 70 The experiments revealed that the reaction of tetrahydroindole 1a with pyrrolines 4b-d bearing the C2-alkyl group (Me, Et, Pr i ) under these conditions proceeded efficiently to afford pyrrolo[1 ,2 :2,3]imidazo[1,5-a]indoles 5b-d in good to high yields (Scheme 2). There is a clear influence of the steric factors of the substituent at position 2 of pyrroline 4 on the yield of product 5: the more sterically compact methyl group compared to isopropyl group gives the product in a higher yield (79% vs. 60%). The presence of a tert-butyl group near the reaction center creates steric hindrance, preventing a more favorable orientation of the reagents during the reaction. In this case, just a trace amount of the target product 5e was detectable ( 1 H NMR spectrum) in the reaction mixture. In addition, the negative effect of substituents in the pyrroline ring on the rate of cycloaddition and product yields is associated not only with steric hindrance, but also with the electron-donating action of alkyl substituents, which stabilizes the emerging positive charge in position 2 of the pyrroline ring. At the same time, the electron-withdrawing substituent at the triple bond of tetrahydroindole 1 had no noticeable effect: the reaction of benzoyl-1a and thenoyl-1b derivatives with 2-methylpyrroline 4b proceeded under these conditions with comparable efficiency (79% and 72% yield). The synthesized pyrrolo[1 ,2 :2,3]imidazo [1,5-a]indoles 5a-f were isolated as a mixture of the Eand Z-isomers in a 4:1 ratio. just a trace amount of the target product 5e was detectable ( H NMR spectrum) in the reaction mixture. In addition, the negative effect of substituents in the pyrroline ring on the rate of cycloaddition and product yields is associated not only with steric hindrance, but also with the electron-donating action of alkyl substituents, which stabilizes the emerging positive charge in position 2 of the pyrroline ring. At the same time, the electron-withdrawing substituent at the triple bond of tetrahydroindole 1 had no noticeable effect: the reaction of benzoyl-1a and thenoyl-1b derivatives with 2-methylpyrroline 4b proceeded under these conditions with comparable efficiency (79% and 72% yield). The synthesized pyrrolo[1′,2′:2,3]imidazo [1,5-a]indoles 5a-f were isolated as a mixture of the E-and Z-isomers in a 4:1 ratio. The reaction of dihydrobenzo[g]indole 2 with pyrroline 4 was expectedly somewhat more reluctant than that with tetrahydroindole 1 (Scheme 3). Under analogous conditions, unsubstituted pyrroline 4a provided the corresponding adduct 6a in a 70% yield (conversion of 2 was 88%). In contrast to the similar reaction with tetrahydroindole (see above), 2-alkylpyrrolines 4b-d led to the formation of pyrroloimidazoles 6b-d only in a 26-44% yield (vs. 60-79% with tetrahydroindole) (conversion of 2 was 35-56%). Pyrroline 4e with tert-butyl at the position 2 gave no even traces of the expected annulation product. An obvious cause of the reaction inhibition is steric repulsion between the benzene ring annulated with the tetrahydroindole moiety and the C2 substituent in pyrroline 4e.
A similar effect of the C2 substituent on annulation was observed in the reaction of benzoylethynylcyclohepta[b]pyrrole 3 with pyrroline 4 (Scheme 4). Pyrrole 3 reacted with pyrroline 4a to form the expected tetracyclic adduct 7a in a 76% yield as an E/Z isomer (4:1). In Me-pyrroline 4b, the yield of adduct 7b slightly decreased (conversion of the starting pyrrole 3 was 82% vs. 90% with pyrroline 4a). The replacement of the methyl group by ethyl or isopropyl ones in pyrroline 4 reduced the product yields to 32-34%. This is probably due to the steric effect of the fused cycloheptyl moiety with a different conformation to cyclohexyl. The reaction of dihydrobenzo[g]indole 2 with pyrroline 4 was expectedly somewhat more reluctant than that with tetrahydroindole 1 (Scheme 3). Under analogous conditions, unsubstituted pyrroline 4a provided the corresponding adduct 6a in a 70% yield (conversion of 2 was 88%). In contrast to the similar reaction with tetrahydroindole (see above), 2-alkylpyrrolines 4b-d led to the formation of pyrroloimidazoles 6b-d only in a 26-44% yield (vs. 60-79% with tetrahydroindole) (conversion of 2 was 35-56%). Pyrroline 4e with tert-butyl at the position 2 gave no even traces of the expected annulation product. An obvious cause of the reaction inhibition is steric repulsion between the benzene ring annulated with the tetrahydroindole moiety and the C2 substituent in pyrroline 4e. Int A similar effect of the C2 substituent on annulation was observed in the reaction of benzoylethynylcyclohepta[b]pyrrole 3 with pyrroline 4 (Scheme 4). Pyrrole 3 reacted with pyrroline 4a to form the expected tetracyclic adduct 7a in a 76% yield as an E/Z isomer (4:1). In Me-pyrroline 4b, the yield of adduct 7b slightly decreased (conversion of the starting pyrrole 3 was 82% vs. 90% with pyrroline 4a). The replacement of the methyl group by ethyl or isopropyl ones in pyrroline 4 reduced the product yields to 32-34%. This is probably due to the steric effect of the fused cycloheptyl moiety with a different conformation to cyclohexyl.   In a number of publications ( [25] and ref. cite therein) concerning the reactions of nitrogen nucleophiles (pyridines, quinolones, indolizines, etc.) with activated alkynes, the reversible formation of 1,3(4)-dipolar complexes (zwitterions) as key intermediates was proved to occur. As follows from Scheme 5, this step is implied to be a major one in the reaction studied and therefore its mechanism does not likely differ much in other details from the commonly accepted ones.
As suggested in article [23], the concerted [3+2] cycloaddition is also not excluded. In a number of publications ( [25] and ref. cite therein) concerning the reactions of nitrogen nucleophiles (pyridines, quinolones, indolizines, etc.) with activated alkynes, the reversible formation of 1,3(4)-dipolar complexes (zwitterions) as key intermediates was proved to occur. As follows from Scheme 5, this step is implied to be a major one in the reaction studied and therefore its mechanism does not likely differ much in other details from the commonly accepted ones.
As suggested in article [23], the concerted [3+2] cycloaddition is also not excluded. Benzo[g]indole scaffold is used in the synthesis of fluorescent organic molecules that have wide biomedical and technical applications [26,27]. Our interest in the photophysics of the synthesized benzo[g]pyrroloimidazoindoles 6 is instigated by the presence of intense long-wavelength (λ abs (max)~410 nm, ε ≈ 40,000 M −1 cm −1 ) electronic absorption bands with maxima in the violet region and blue photoluminescence, which could make them attractive materials in optoelectronics for blue organic light-emitting diodes (OLEDs). It is clear that the optoelectronics-related properties of benzo[g]pyrroloimidazoindoles 6a-d are associated with the benzo[g]indole fragment in their structure, as most conjugated and enriched p-electrons. Since compounds 6a-d differ from each other only by alkyl substituent, their photophysical properties should not be noticeably different. In this work, preliminary experimental and theoretical studies of the spectral and photophysical properties were performed using (E)-2-(5,6,10,11,12,12a-hexahydro-8H-benzo[g]pyrrolo[2',1':2,3]imidazo[1,5a]indol-8-ylidene)-1-phenylethan-1-one (6a) as an example.
In liquid media, despite the ππ*-character and strong oscillator strength of the fluorescent S 1 state (f = 1.09), as well as the favorable relative position of the forbidden state S 2 (n O π*+ππ*, f = 0.04), the fluorescence quantum yield (Φ F ) of the synthesized compound turned out to be low (Tables 2 and 3, Figure 2). This is most likely explained by the effective intersystem crossing (ISC) between the fluorescent S 1 (ππ* ST , 3.54 eV) and the closest to it lower energy triplet state T 4 , (n O π*+ππ*, 3.43 eV) with different orbital types according to El Sayed's rules [28] (Table 3, Figure 2).  S0 → T4 (nOπ*+ππ*) S0 → S1 (ππ*CT) S0 → S2 (nOπ*+ππ*) On the other hand, it is known that in solid media organic molecules with a small singlet-triplet (S-T) gap and a donor-acceptor (D-A) character can exhibit thermally activated delayed fluorescence (TADF) [29,30]. The mechanism is based on the thermal upconversion of the triplet excitons into singlets via the reverse intersystem crossing. TADF has gained considerable interest in recent years, since the materials exhibiting TADF can act as high-performance emitters in OLEDs [31,32]. Since quantum chemical calculations (Table 3) predict that benzo[g]pyrroloimidazoindoles have small S-T splitting (ΔEST = 0.11 eV for 6a), as well as the fact that they are D-A type compounds (donor-pyrrole ring and acceptor-benzoyl fragment), then according to the literature criteria, these compounds can be good candidates for TADF emitters for OLEDs. In this regard, in the near future we plan to carry out spectral-luminescence and kinetic studies of benzo[g]pyrroloimidazoindoles in solid media.

General Information
NMR spectra were recorded from solutions in CDCl3 on Bruker DPX-400 and AV-400 spectrometers (Bruker, Billerica, MA, USA) (400.1 MHz for 1 H, 100.6 MHz for 13 C, and 40.5 MHz for 15 N). Chemical shifts (δ) were quoted in parts per million (ppm). The On the other hand, it is known that in solid media organic molecules with a small singlet-triplet (S-T) gap and a donor-acceptor (D-A) character can exhibit thermally activated delayed fluorescence (TADF) [29,30]. The mechanism is based on the thermal upconversion of the triplet excitons into singlets via the reverse intersystem crossing. TADF has gained considerable interest in recent years, since the materials exhibiting TADF can act as high-performance emitters in OLEDs [31,32]. Since quantum chemical calculations (Table 3) predict that benzo[g]pyrroloimidazoindoles have small S-T splitting (∆E ST = 0.11 eV for 6a), as well as the fact that they are D-A type compounds (donor-pyrrole ring and acceptorbenzoyl fragment), then according to the literature criteria, these compounds can be good candidates for TADF emitters for OLEDs. In this regard, in the near future we plan to carry out spectral-luminescence and kinetic studies of benzo[g]pyrroloimidazoindoles in solid media.
UV/Vis absorption spectra were measured on a Lambda-35 (Perkin-Elmer, Waltham, MA, USA) spectrophotometer. Fluorescence spectra were measured on a FLSP-920 combined steady-state and time-resolved fluorescence spectrometer (Edinburgh Instrument, Livingston, UK). All the solvents employed for the spectroscopic measurements were of UV spectroscopic grade (Merck, Rahway, NJ, USA). For fluorescence measurements, dilute solutions with an absorbance of less than 0.1 (at 1 cm optical path length) at the absorption maximum were used. The fluorescence measurements were performed with a 90 • standard geometry. The fluorescence quantum yields (Φ F ) of 6a were evaluated relative to anthracene (Φ F = 0.27 in EtOH as the reference and was corrected from the dependence of the refractive index of the solvent [33]). The temperature for fluorescence measurements was kept constant at 298 K. All quantum chemistry calculations were carried out using the Gaussian 09.B.01 program package [34]. The ground-state (S 0 ) geometry optimizations and the vertical excitations S 0 → S i (i = 1-5) at the S 0 geometry were calculated with the TD-CAMB3LYP method, with a split valence with polarization SVP basis set. An analysis of the nature of the transitions, fraction of electron charge transferred (q CT ), distance of charge transfer (D CT ), and dipole moment variation at excitation (∆µ) was carried out using Multiwfn 3.8. software [35].
IR spectra were obtained on a Varian 3100 IF-IR spectrometer (Digilab LLC, USA) (400-4000 cm −1 ) as thin films dispersed from CDCl 3 . Mass spectra of synthesized compounds were recorded on a GCMS-QP5050A spectrometer from Shimadzu Company. High-resolution mass spectral analyses were performed from acetonitrile solution with 0.1% HFBA on an HPLC Agilent 1200/Agilent 6210 TOF instrument equipped with an electrospray ionization (ESI) source (Agilent, USA). Melting points (uncorrected) were measured on a melting point apparatus SGW-X-4 (China). Thin-layer chromatography was carried out on Merck silica gel 60 F254 pre-coated aluminum foil sheets which were visualized using UV light (254 nm). Column chromatography was carried out using slurry-packed Alfa Aesar silica gel (SiO 2 ), 70-230 mesh, pore size 60 Å.

Preparation and Characterization of Substrates
Pyrrolines 4a [36] and 4c-e [37] were prepared by following the same procedure as described in the literature.

General Procedure for the Synthesis of Compounds 5-7
To a solution of ethynylpyrrole 1-3 (0.5 mmol) in the mixed solvent of MeCN (0.5 mL) and THF (0.5 mL), pyrroline 4 (0.5 mmol) was added and the resulting mixture was stirred at 70 • C in an oil bath for 8 h. Then, the solvents were removed under reduced pressure, and residue was purified by column chromatography (SiO 2 , eluent: hexane/Et 2 O 1:1, v/v) to give adducts 5-7.